Novel 6-chloro-17alpha-haloethynyl-19-norandrostadienes and processes



United States Patent Ofitice 3,072,646 Patented Jan. 8, 1963 material utilized is the 3-methoxy-2,5(l0)-androstadienel7-one which has the following structural formula:

A o mtU It has been found that the above starting material will react with a haloethyne to form the corresponding 17ozhaloethynylfi-methoxy-LS 10) androstadiene 17B 01, which has the following structure:

wherein X stands for chloro, bromo or fiuoro.

In a preferred embodiment of our inventon, the haloethyne is formed in situ by the reaction of a 1,2-dihaloethylene (preferably the cis form) and methyl lithium. For example, the l7a-chloroethynyl-3-methoxy 2,5 10)- androstadiene-lm-ol is prepared by adding a solution of cis-1,2-dichloroethylene in ether to a solution of methyl lithium at about 0 C. in ether. The reaction mixture is stirred under nitrogen for 1-2 hours, 3-methoxy-2, 5(10)-androstadiene-17-one is added, and stirring is continued for several hours longer.

The l7u-haloethynyl-3-methoxy-2,5 10)-androstadiene- 175-01 is converted into the l7ot-ha-loethynyl-17,8-hydroxy- 19-nor-4-androstene-3-one (i.e. the 21-halonorethisterone) which has the following formula:

enesulfonic acid in acetone solution is left standing at room temperature overnight.

The 17 a-haloethynyl- 17fi-hydroxy-19-nor-4-androstene- 3-ones are converted into the 3-en0l ethers (i.e. the 3- alkoxy-17a-haloethynyl-19-nor-3,S-androstadiene-l7fi-ols) which have the following formula:

HO CECX wherein X stands for chloro, bromo or fiuoro, and R is an alkyl group, by stirring together a mixture of the steroid and an alkyl orthoformate in dioxane solution in the presence of a strong acid catalyst, for example, a mineral acid, or an organic sulfonic acid.

In a preferred embodiment of our invention, the novel 3-enol ethyl ethers of the 17a-haloethynyl-175-hydroxy- 19-nor-4-androstene-3-ones are prepared by adding ethyl orthoformate and p-toluenesulfonic acid to a solution of the steroid in dioxane and stirring together at room temperature. The acid catalyst is then neutralized with a base such as pyridine. The 3-enol n-butyl ethers of the l7a-haloethynyl-l7B-hydroxy l9 nor 4 androstene-3- ones are prepared by stirring together a mixture of the steroid and n-butyl orthoforrrrate with 2,4-dinitrobenzenesulfonic acid in dioxane solution overnight at about 30 C. The acid catalyst is then neutralized with a base such as pyridine.

The 6-chloro-17a-haloethynyl-17B-hydroxy-19=nor-4,6- androstadiene-B-one is prepared from the 3-enol ethyl ether of the 17a-haloethynyl-17B-hydroxy-19-nor-4-androstene-3-one by reaction first with N-bromosuccinimide to give 6/8-bromo 17a haloethynyl-l7fi-hydroxy-l9-nor-4- androstene-3-one which has the following formula:

no osox HO CECX wherein X is chloro, bromo or fiuoro. The dehydrogenation is brought about by heating a solution of the steroid in a solvent such as dimethylformamide with lithium bromide and lithium carbonate for several hours at about C.

The above compound is then oxidized to the 60:,7eepoxy 17cc haloethynyl 17,6 hydroxy-19-nor-4-androstene-3-one which has the following structure:

wherein X is chloro, bromo or fluoro, suitably by treating a solution of the steroid in a solvent such as benzene w-ith perbenzoic acid in the dark at room temperature for about 60-70 hours.

A solution of the Gems-epoxy-17a-haloethynyl-l7 3-hydroxy-19-nor-4-androstene-3-one in an organic solvent is treated with HCl at room temperature to form the 6-chloro-17a-haloethynyl-17p-hydroxy-19 nor 4,6 androstadiene-3-one which has the following formula:

wherein X is chloro, bromo or fluoro.

17a-haloethynyl-3-methoxy-2,5 l0)-androstadiene-17,8- 01 is converted into 17a-haloethynyl-171S-hydroxy-5(10)- androstene-3-one (21-halo-Enovid) which has the f01l0W1 ing formula:

wherein X stands for chloro, bromo 0r fluoro, by reaction with a weak organic acid such as acetic acid. For example, a mixture of the steroid and glacial acetic acid in an aqueous solution of absolute ethanol and dioxane is left standing at room temperature for several hours.

The l7a-haloethynyl-17fi-hydroxy-4,9-androstadiene-3- one which has the following formula:

H0 CEO-X A solution consisting of 1.7g. (1.32 cc.) of cis-1,2-

dichloroethylene in 10 cc. of sodium dried ether is added over 0.5 hour at 0 C. to 3 cc. of a 1.4 N solution of methyl lithium (prepared by adding lithium to methyl iodide in dry ether solution under nitrogen at about 10 C.) in 25 cc. of sodium dried ether. The reaction mixture is stirred at room temperature under nitrogen for an additional 1 /2 hours, followed by the addition, over a 15-minute period, of mg. of 3-methoxy-2,5(l0)- androstadiene-17-one in 4 cc. of sodium dried ether. The mixture is left stirring at room temperature overnight, poured into ice water and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on 10 g. of basic alumina. The product is eluted with petroleum etherzether 8:2. Crystallization from acid-free methanol affords 48 mg. of 17e-chloroethynyl- 3-methoxy-2,5(10)-androstadene 17,8 ol, M.P. 112- 115 C.

LR. mil? 2.80, 4.48, 6.02, 6.12;;

Analysis.--Calculated for C H O Cl: C, 72.71; H,

7.85. Found: C, 72.85; H, 8.13.

In accordance with the above procedures, but using 1,2- dibromoethylene in place of 1,2-dichloroethylene, there is obtained the 17a-bromoethynyl-3-methoxy-2,5(l0)- androstadiene-l7 3-ol.

In accordance with the above procedure, but using 1- chloro-Z-fluoroethylene in place of 1,2-dichloroethylene, there is obtained a mixture of the l7u-chloroethynyland the l7u-fluoroethynyl-3-methoxy-2,5( 10) -androstadiene- 17 8-01, which compounds are separated by chromatography.

Example 2 A solution consisting of 10 mg. of l7e-chloroethynyl- 3-methoxy-2,5(l0)-androstadiene-l7B-ol, 2 cc. of acetone and 2 mg. of p-toluenesulfonic acid is left standing at room temperature overnight. The reaction mixture is then poured into ice water and extracted with ether. The ether extract is washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Crystallization from ethyl acetate affords 17mchloroethynyl-17fi-hydroxy-19-nor-4-androstene 3 one, M.P. -190.

LR. Xfigi? 2.95, 4.50, 6.10, 6.21;;

In accordance with the above procedure, but starting with the l7a-bromoethynylor 17a-fiuoroethynyl-3- methoxy-2,5(l0)-androstadiene-l7fl-ol in place of the 17a-choroethynyl 3 methoxy 2,5 (l0)-androstadiene- 1718-01 there is obtained as products the corresponding 17a-bromoethynylor 17a-fluoroethynyl-17fl-hydroxy-l9- nor-4-androstene-3-one.

Example 3 To a solution of 100 mg. of 17a-chloroethynyl-17fihydroxy-19-nor-4-androstene-3-one in 3 cc. of dioxane is added 2 cc. of ethyl orthoformate and 10 mg. of ptoluene-sulfonic acid. The reaction mixture is stirred at room temperature for 3 hours and 1 cc. of pyridine is added, followed by the dropwise addition of 5 cc. of water. The aqueous phase is separated and extracted with benzene. The organic extracts are washed with a sodium bicarbonate solution and then with water until the washings are neutral. The organic phase is dried over sodium sulfate and concentrated in vacuo to give 3- ethoxy-17e-chloroethynyl-19-nor-3,5-androstadiene 17p. 01.

LR. Am? 2.86, 4.50, 6.05, 6.15 1.

In accordance with the above procedure, but starting with the 17a-bromoethynylor the 17a-fluoroethynyl-l7B- hydroxy-19-nor-4-androstene-3-one in place of the 17mchloroethynyl-l7B-hydroxy-l9-nor-4-androstene 3 one there are obtained as products the corresponding 17a- A mixture of 100 mg. of 17a-chloroethynyl-17fi-hydroxy-19-nor-4-androstene-3-one, 0.06 g. of 2,4-dinitrobenzenesulfonic acid, 3 ml. of dry dioxane and 0.25 ml. of freshly distilled n-butyl orthoformate are stirred overnight at 30 C. The acid catalyst is then neutralized by addition of 0.1 ml. of pyridine. The reaction mixture is diluted with water and extracted with ether. The combined ether extracts are washed with water, dried and evaporated under reduced pressure. The residue is chromatographed over alumina (alkaline) and eluted with mixtures of ether and petroleum ether to separate 3-butoxy- 17a-chloroethynyl-19-nor 3,5 androstadiene- 17 8-01.

In accordance with the above procedure, but starting with the l7a-bromoethynylor the 17a-fiuoroethyny1- 173-hydroxy-19-nor-4-androstene-3-one in place of the 17a-chloroethynyl-17fi-hydroxy-l9-nor 4 androstene-3- one there are obtained as products the corresponding 17a-bromoethynylor the 17a-fluoroethynyl-3-butoxy-19- nor-3,5-androstadiene-175-01.

Example 5 A solution consisting of 1 g. of 3-ethoxy-17u-chloroethynyl-19-nor-3,5-androstadiene-17,8-01, 700 mg. of sodium acetate, 5 ml. of water and 40 ml. of acetone is cooled to C. and 1.07 g. of N bromosuccinimide and 0.83 ml. of acetic acid is added. The mixture is stirred for 3 hours at C. and then poured into water to yield the 6I3-bI'OITlO-170t-ChiOI'OEthYHY1-17/3-hydI'OXy-19- nor-4-androstene-3-one.

Treatment of 6,B-bromo-Not-chloroethynyl-17B-hyd oxy-l9-nor-4-androstene-3-one (1.0 g.) with 1.0 g. of lithium bromide, 500 mg. of lithium carbonate and 20 ml. of dimethylformamide for 5 hours at 120 C., fol lowed by dilution with ice water and filtration afiords 17achloroethynyl-17fl-hydroxy 19-n0r 4,6 androstadiene-3- one.

A solution consisting of 675 mg. of Hot-chloroethynyl- 17/3-hydroxy-19-nor-4,6-androstadiene-3-one, 30 ml. of 0.2 N perbenzoic acid dissolved in benzene, and 30 ml. of ether is allowed to stand at room temperature in the dark for 68 hours. The product is washed with acidified sodium b-isulfite solution, water, 2.5 N potassium hydroxide solution and water. The material is dried and concentrated in vacuo. The crude 6m,7a-epoxy-17a-ch1oroethynyl-l7B- hydroxy-l9-nor-4-androstene-3-one is used directly in the next step.

The 6a,7a epoxy 17a chloroethynyl 17,8 hydroxy 19 nor 4 androstene 3 one dissolved in 20 ml. of 0.4 N hydrochloric acid in chloroform, is allowed to stand for 5.5 hours at room temperature, and then subsequently poured into iced sodium bicarbonate solution. The product is extracted with chloroform, dried, and concentrated in vacuo. Chromatography on acidwashed alumina (20 g.) and elution with ether-petroleum ether mixtures affords the 6-chloro-Una-chloroethynyl-17B- hydroxy-l9-nor-4,6-androstadiene-3-one.

In accordance with the above procedures, but starting with the 3-ethoxy-17a-bromoethynyl- (or the 17a-fluoroethynyl)-19-nor-3,S-androstadiene-17B-ol in place of the 3 ethoxy 17m chloroethynyl 19 nor 3,5 androstadiene 17B 01 there are obtained as products the corresponding 6-chloro-17a-brornoethynyl- (or the 17erfluoroethynyl)-17;3-hydroxy-19-nor-4,6 androstadiene-3- one.

Example 6 T o a solution of 160 mg. of 17ot-chloroethynyl-3- methoxy-2,5()-androstadiene-17/8-ol in 1.6 cc. of dioxane and 7.2 cc. of absolute ethanol is added 3.2 cc. of glacial acetic acid, and immediately thereafter, 1.6 cc. of water. This reaction mixture is left standing at room temperature for 5 hours. It is then poured into an ice/sodium bicarbonate solution, allowed to stand until the mixture is basic and extracted with benzene. The benzene extracts are washed with water until the washings are only slightly basic and then dried over anhydrous potassium carbonate, filtered and concentrated in vacuo using a water bath at 3050 C. By crystallization from ether, about mg. of Nor-chloroethynyl-17p-hydroxy-5(10)- andros'tene-3-one is obtained. U.V. no max.;

I.R. X232 2.98, 4.50, 5.90 4

In accordance with the above procedures, but starting with the 17a-bromoethynylor the l7a-fluoroethynyl-3- methoxy-2,5(10)-androstadiene-17B-ol in place of the 170:- chloroethynyl-3-methoxy-2,5 10) -androstadiene-17[i 01 there are obtained as products the corresponding 17abromoethynylor l7e-chloroethynyl-17,8-hydroxy-5 10) androstene-3-one.

Example 7 To mg. of 17a-chloroethynyl-17p-hydroxy-5 (10)- androstene-3-one in 5 cc. of pyridine is added one equivalent of bromine. The reaction is stirred for two hours at room temperature, poured into ice-water and extracted with ether. The ether extract is washed with water, dried over sodium sulfate, and concentrated in vacuo to yield 17a-chloroethynyll 7,8-hydroxy-4,9=androstadiene-3-one.

In accordance with the above procedures, but starting with the 17u-brornoethynylor the 17ot-fluoroethynyl-17phydroxy-5(10)-androstene-3-one in place of the 17a-ch1oroethynyl-17fl-hydroxy-5(10)-androstene-3-one there are obtained as products the corresponding 17oc-blOII106thY- nylor the 17ot-fiuoroethynyl-17/3-hydroxy-4,9-androstadiene-3-one.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. 17a haloethynyl 17,8 hydroxy 19 nor 4,6- androst-adiene 3 one.

2. 6a,7u-epoxy 17a haloethynyl 175 hydroxy- 19 nor 4 androstene 3 one.

3. 6 chloro a haloethynyl 17,9 hydroxy 19- nor 4,6 androstadiene 3 one.

4. 6 chloro 17a chloroethynyl 17p hydroxy- 19 nor 4,6 androstadiene 3 one.

5. Process for the preparation of 6fl-bromo-17oc-haloethynyl 17,8 hydroxy 19 nor 4 androstene 3- one which comprises reacting a solution of 3-ethoxy-17ah'aloethynyl-l9-nor-3,5-androstadiene-175-01 in an organic solvent with N-bromosuccinimide in the presence of acetic acid and sodium acetate.

6. Process for the preparation of 17a-haloethynyl-17B hydroxy-19-nor-4,6-androstadiene-3-one which comprises heating a solution of 65-bromo-17ot-haloethynyl-17B-hydroxy-l9-nor-4-androstene-3-one in an organic solvent with lithium bromide and lithium carbonate.

7. Process for the preparation of 5,6-epoxy-17a-haloethynyl 17/8 hydroxy 19 nor 4 androstene 3 one which comprises oxidizing 17x-haloethynyl-17B-hydroxy- 19-nor-4,6-androstadiene-3-one with perbenzoic acid.

8. Process for the preparation of 6-chlor-o-l7a-haloethynyl 17,6 hydroxy l9 nor 4,6 androstadiene- 3 one which comprises treating a solution of 60,7aepoxyl7rx-haloethynyl- 1 713 hydroxy-19-nor-4-androstene- 3-one with hydrogen chloride.

9. Process for the preparation of l7a-ha1oethynyl-17B- hydroxy-5(10)-androstene-3-one which comprises reacting 17a haloethynyl 3 methoxy 2,5(10) androstadiene 17B 01 with acetic acid.

No references cited. 

2. 6A,7A-EPOXY - 17A - HALOETHYNYL - 17B - HYDROXY19 - NOR - 4 - ANDROSTENE - 3 - ONE. 